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Thioridazine
Thioridazine is a piperidine phenothiazine antipsychotic drug and is used in the treatment of schizophrenia and psychosis. Thioridazine is a typical low-potency neuroleptic that is slighly less potent than chlorpromazine. It has a halflife of 7 to 13 hours. (Other sources have 16 to 24 hours.) It has the advantage of a low incidence of early and late extrapyramidal side-effects (tardive dyskinesia). In this regard it is very similar to the atypical neuroleptic clozapine (Clozaril®). Thioridazine has also intrinsic mild to moderate antidepressive properties. It has antiemetic properties. Sedation is said to be less pronounced compared with chlorpromazine. Indications Previous additional indications were agitated depression, tension and anxiety linked to alcohol withdrawal and dysphoria of epileptic patients. It had even (Melleretten® in Europe) an indication for the treatment of psychosis in children and adolescents (10mg to 60mg daily). It was also given off-label for the treatment of insomnia and for alleviation of opiate withdrawal. Thioridazine is known to kill multidrug-resistant mycobacterium tuberculosis and MRSA at clinical concentrations.. Metabolism Thioridazine is a racemic compound with two enantiomers, both of which are metabolized, according to Eap et al, by CYP2D6 into (S)- and ®-thioridazine 2-sulfoxide, better known as mesoridazine, and into (S)- and ®-thioridazine-5-sulfoxide. Mesoridazine is in turn metabolized into sulforidazine. Thioridazine is an inhibitor of CYP1A2 and CYP3A2 Side Effects Central nervous system side-effects occur. These are mainly drowsiness, dizziness, fatigue, and vertigo. Early and late extrapyramidal side-effects are seen only infrequently (less than 1% altogether). There is no clear dose-effect relationship, as with higher doses anticholinergic effects of thioridazine become more prominent. Thioridazine causes also an unusual high incidence of impotence and anorgasmia due to a strong alpha-blocking activity. Painful ejaculation or no ejaculation at all is also sometimes seen. Autonomous side-effects (dry mouth, urination-difficulties, obstipation, induction of glaucoma, postural hypotension, and sinus tachycardia) occur obviously less often than with most other mildly potent antisychotics. Thioridazine is no longer recommended as first-line treatment due its side-effect of prolonging the QT interval on the EKG. Thioridazine-5-sulfoxide is responsible for the (ventricular tachycardia, torsades de pointes) according to Heath, Svensson and Martensson. Also, the serious and sometimes fatal blood damage agranulocytosis is seen more frequently (approximately 1/500 to 1/1,000 patients) with thioridazine than with other typical phenothiazines (1/2,000 to 1/10,000 patients). Thioridazine if given over a prolonged time and in high doses can be stored in the ocula and the retina of the eyes and in the heart muscle. Clinical consequences (disturbed or blurred vision) are rare. Discontinuation It is advisable to withdraw thioridazine gradually and not abruptly to avoid unpleasant withdrawal symptoms (agitation, insomnia, anxiety). Another neuroleptic may be introduced to the theraputic regime step by step (overlapping), if needed. If sudden withdrawal of thioridazine is necessary, withdrawal symptoms can also be alleviated with the benzodiazepines lorazepam (Ativan®) 1mg-2mg, alprazolam (Xanax®) 0,5mg prn or clonazepam (Klonopin®) 0,5mg to 2mg prn (as needed) for up to 2 weeks (not longer to avoid addiction). History The manufacturer Novartis/Sandoz/Wander of the brands of thioridazine, Mellaril® in the USA and Canada and Melleril® in Europe, discontinued the drug worldwide in June 2005. The usual dosage was 50mg per day for mild cases to 600-800 mg per day for severely disturbed patients. Thioridazine may still be available from other manufacturers as a generic drug with the precaution that it is used only in psychotic patients refractory to other forms of drug treatment. EKG-monitoring and frequent white blood cell counts are required before initiating therapy and in close intervalls afterwards. References and End Notes # Amaral L, Viveiros M, Molnar J. "Antimicrobial activity of phenothiazines." In Vivo. 2004 Nov-Dec;18(6):725-31. PMID 15646813 # PubChem Substance Summary: Mesoridazine National Center for Biotechnology Information. # Eap CB, Guentert TW, Schaublin-Loidl M, Stabl M, Koeb L, Powell K, Baumann P. "Plasma levels of the enantiomers of thioridazine, thioridazine 2-sulfoxide, thioridazine 2-sulfone, and thioridazine 5-sulfoxide in poor and extensive metabolizers of dextromethorphan and mephenytoin." Clinical Pharmacology & Therapy. 1996 Mar;59(3):322-31. 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